Mom's Immune System Influences Baby’s Salience Network

It’s long been known that mothers who experience a
heightened immune response during pregnancy, generally in the form of excess
inflammation due to infection, have children who are at higher risk for
neurodevelopmental disorders like autism and schizophrenia (See “Maternal
Flu Infection May Lead to Increased Risk of Schizophrenia in Child”).
Yet, despite intense study in animal models, the mechanisms of the relationship
between the maternal immune system and fetal brain development are not well
understood—particularly in humans. Now, a collaborative, longitudinal study
suggests that an increased level of inflammatory proteins in mothers is
surprisingly linked to greater connectivity in the salience network, a key
network of brain regions that help direct attention and focus, in offspring—as
well as higher score on a cognitive ability metric at 14 months of age.

Understanding maternal
immune activation

Epidemiological studies have long suggested that
infectious disease epidemics, ranging from influenza to toxoplasmosis, are
often followed by an increase in the
diagnosis of neurodevelopmental disorders in children who were born
during or soon after such outbreaks. These diseases don’t have much in
common—except that they all trigger a pregnant mother’s immune response. Jun
Huh, an immunobiologist at Harvard University, says scientists now understand
that this phenomenon, called maternal immune activation, has the power to make
long-term changes to the brain development of offspring.

“There are many studies that clearly show that if a
pregnant mother is severely ill, or hospitalized during pregnancy, particularly
during the later stages of pregnancy like the third trimester, there is an
increased chance that the mother will produce a child with a neurodevelopmental
disorder,” he says. “And, thanks to animal models, we now see that the maternal
immune activation is due to inflammatory processes.”

But what triggers those inflammatory processes, exactly,
leading to issues in fetal brain development? Marisa Spann, a professor of
medical psychology at the Columbia University Medical Center, says that there
are likely many factors.

“There are multiple experiences that may trigger these
pathways—infection, nutrition, stress, environmental toxins,” she says. “Anything,
essentially, that Mom is exposed to, the fetus will also experience and can
result in changes to brain development. In order to understand how maternal immune
activation influences the brains of babies, we need is to understand how each
of these factors may work in isolation and then build a model that can put them
together and help us understand how they may work in combination to lead to
these outcomes.”

Following brain development
over time

To start to create such a model, Spann and colleagues
followed thirty-six pregnant adolescents, aged 14 to 19, through their first
pregnancy. They measured two immune proteins, interleukin-6 (IL6) and
C-reactive protein (CRP), known to be linked to the inflammatory response,
during the final trimester of pregnancy. They also took measures of the
mother’s offspring: heart rate during the final trimester of gestation,
neuroimaging data of the baby’s brain, focusing on the salience network, at a
few months of age, and cognitive ability at 14 months of age. The researchers found that elevated levels of IL6 and CRP
were linked to greater connectivity in the salience network of offspring, as
well as increased cognitive ability; it’s not clear what this means for
function. The results
were published in the March 14 issue of the Journal of Neuroscience.

Bradley Peterson, M.D., director of the Institute for
the Developing Mind, and Spann’s co-author, says the group used teenaged
mothers in the study since epidemiological evidence suggests they are more
susceptible to maternal immune activation. But he hypothesizes that they would
see similar results in older mothers who experience amplified inflammation
during pregnancy as well.

“This is a high-risk cohort that is more likely to see
this kind of immune activation. But there are so many issues that can trigger
this inflammation: obesity, dietary factors, infections, stress,” he says. “We
would expect to see this same result in other groups of mothers. But it’s a
hypothesis that would have to be confirmed and replicated.”

Spann says she was initially surprised that higher
levels of inflammatory proteins were linked to what appear to be better
outcomes: better connectivity of the salience network in infants as well as
higher scores on a developmental battery at 14 months. She’d like to do more
work to better understand the association, especially as it is not clear that
this increased connectivity is necessarily a boon for brain development across
the lifespan.

“The brain, at this point, is still in such an active
period of growth and development,” she says. “It’s very possible that both
progressive and regressive experiences are happening all at the same time. It’s
something we would like to look at – I’d love to follow these kids and see the
later cognitive implications of this prenatal exposure to inflammation. But our
results do suggest that a mother’s inflammatory response does have both short-
and long-term influences on her child’s brain and behavior.” Increased
connectivity might not be beneficial in the long term, for example.

Putting the pieces
together

Huh, whose own laboratory recently published
a study in Nature showing
that maternal gut bacteria likely influence maternal immune activation, says
that researchers across the globe are discovering new insights into different
factors that mediate inflammation levels in pregnant mothers, thereby
potentially affecting the brain development of offspring.

“Certainly, there are important genetic contributions to
these brain pathologies,” he says. “But we are clearly showing that there are
important environmental contributions to neurodevelopmental disorders as well,
one of which is inflammation. If we can identify and get more information about
the players that influence this inflammation, we have the opportunity to possibly
prevent some of these problems.”

Spann agrees, but adds that her study as well as other
work in human populations bolsters the idea that attending to maternal health
during pregnancy is crucial to healthy brains and healthy behavior in offspring.
To offer more concrete recommendations, though, more work needs to be done. Both
she and Peterson would like to continue to follow pregnant mothers and their
children to better understand the different factors that underlie maternal
immune activation. Peterson says that translational studies like theirs help
provide a link between the epidemiological work and neurobiological studies
done in animal models.

“Our study is another piece of the puzzle
regarding maternal immune activation that lends additional support to the idea
that the immune system really is a key mediating pathway for some of these
adverse outcomes,” he says. “And our findings set the stage to support doing
further translational research, looking at larger and more representative
samples of human beings and following children further out in development to
understand how a variety of potential stressors may be relevant to the
long-term well-being of babies.”